Project Summary: Project 4 ? Linking Spinal Circuits to Behavior Despite the critical role forelimb movements play in our interaction with the world, little is known about how specific neural circuits control the precision, speed, and fidelity of these behaviors. While most studies of forelimb movement explore descending motor command pathways, the neural architecture of the cervical spinal cord that supraspinal pathways ultimately recruit to execute dexterous forelimb movement remains mysterious. To address this challenge, two central questions will be explored: 1) How do spinal networks that control rhythmic pattern generation transition to coordinate non-rhythmic movements, which represent the majority of forelimb motor behaviors? 2) How are these spinal circuits modified to control more complex joint movements and achieve forelimb dexterity? Project 4 will bridge the anatomical, physiological, and molecular delineation of motor circuits in the cervical spinal cord (Projects 2 and 3) with the forelimb behaviors they control. This functional information will be used to develop models of spinal circuitry (Project 1) and build a multimodal atlas of the cervical spinal cord (Data Core). While genetic tools in mice have provided a means to define the organization and function of neural circuits, major impediments to exploring the neural basis of skilled forelimb control remain: a) standardized assays for probing mouse forelimb behaviors are few; and b) the lack of electrophysiological access to spinal motor circuits in behaving animals precludes the ability to define how the activity of these circuits corresponds with behavioral output. This Project proposes three major Aims that will address these obstacles. Aim 1 will develop and apply sensitive behavioral assays and electromyography (EMG) recording from forelimb muscles to provide more comprehensive and empirical experimental access to motor control across forelimb joints during defined behaviors. Aim 2 will apply modern molecular-genetic perturbation to investigate the functional organization of pre-motor interneuron networks that modulate the activity of forelimb motor neurons and orchestrate movement. Aim 3 will develop novel approaches for recording from the spinal cord of animals performing forelimb movements, overcoming a critical barrier to defining how spinal neural activity correlates with movement, and how this activity is affected by targeted perturbation. By simultaneously examining each major step in the pathway, from spinal neural circuit activity, to muscle recruitment, to limb kinetics and kinematics, this work will generate a functional map of forelimb motor circuits and enable predictive models of forelimb control to be tested and refined. Ultimately, these advances will provide insight into the neural roots of movement more generally, and help to lay the foundation for better diagnosis and treatment of motor deficits caused by injury or disease.